tbuckley/cabot-search huggingface dataset:
INNV-12. DEMOGRAPHICS, PRESCRIBING PATTERNS, AND SATISFACTION OF HEALTHCARE PROVIDERS WHO PRESCRIBE TUMOR TREATING FIELDS (TTFIELDS) THERAPY TO PATIENTS WITH GLIOBLASTOMA
Authors: Shermona Shockley, P Gage Gwyn, Elena Palmesino, Eleni Batzianouli, Heather Johnson
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND TTFields are electric fields that disrupt cellular processes critical for cancer cell survival. TTFields therapy was approved for recurrent and newly diagnosed glioblastoma (GBM) in 2011 and 2015, respectively, and here we report on the demographics, prescribing patterns, and satisfaction of TTFields therapy from healthcare providers (HCPs) throughout the US. METHODS In 2022, HCPs completed surveys regarding their satisfaction in prescribing TTFields therapy to patients with GBM, based on their experiences with the device system (NovoTTF-200A; Novocure® GmbH). RESULTS Overall, 32 HCPs completed the survey; all respondents had prescribed TTFields therapy in the prior 6 months. Respondents were physicians (66%), nurse practitioners/advanced practice registered nurses (22%), and physician’s assistants (12%); specialties included radiation oncology (50%), neuro-oncology (41%), medical oncology (7%), and neurosurgery (3%). A balance in practice settings was represented: academic/university (34%), cancer specialist center (28%), private practice (22%), and community (16%). Overall, 44% of HCPs reported having ≥37 months experience prescribing TTFields therapy. Most respondents (69%) had prescribed TTFields therapy to 1–5 patients, with 75% reporting no change in volume of treated patients over the past 6 months. Satisfaction was high for patient support services (66% very satisfied; 16% satisfied) and prescription support processes (66% very satisfied; 31% satisfied). There were high overall satisfaction levels with the use of virtual educational resources, certification training, and educational materials for providers and for patients (≥88% very satisfied/satisfied rating each). RESULTS were similar for academic and non-academic respondents. CONCLUSION These survey data provide insights regarding the demographics and prescribing patterns of HCPs providing TTFields therapy to patients with GBM. These data indicate a high degree of satisfaction with the prescription process and support. Increasing awareness of support programs and resources remains important in overcoming barriers to TTFields therapy initiation to optimize patient experience.
RADT-20. STEREOTACTIC RADIOSURGERY FOR 15 OR MORE BRAIN METASTASES
Authors: Rituraj Upadhyay, Joshua Palmer, Haley Perlow, Jonathan Schoenhals, Jayeeta Ghose, Prajwal Rajappa, Dukagjin Blakaj, Sasha Beyer, John Grecula, Austin Sim, Douglas Hardesty, J Bradley Elder, Arnab Chakravarti, Evan Thomas, Raju Raval
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Patients with ≥ 15 brain metastases(BM) continue to be treated with whole brain radiation therapy(WBRT), despite poor neurocognitive outcomes. We analyzed our institutional experience of treating these patients with stereotactic radiosurgery(SRS), with the aim of evaluating safety, cognitive outcomes, and survival. METHODS Patients who received SRS for ≥ 15 BMs in 1-5 fractions from 2014-2022 using the previously described single isocenter multi-target technique were included. Cognitive outcomes were objectively evaluated using serial Patient-Reported Outcome Measurement Information System(PROMIS) scores. RESULTS A total of 124 patients treated with LINAC-based SRS were included. The mean and median number of lesions treated per patient was 24.8 and 20, respectively (range 15 – 94). Most common primary histologies were lung(47.6%), melanoma(21.0%), and breast(14.5%). The median SRS dose was 24 Gy(range 18 – 30 Gy). The rate of any grade radiation necrosis (RN) and ≥ grade 3 RN were 15.3% and 3.2% respectively. New onset seizures were seen in 2.4% and alopecia in 2.4%. Median follow-up was 5.1 months(m). When cognitive data were available, 25 of 31 patients had a stable or improved PROMIS score. The 12m local control was 97.6% while overall intracranial control was 20.8%. One-year freedom from neurological death, leptomeningeal disease, and salvage WBRT were 85.6%, 87.6% and 71.7% respectively. Median overall survival(OS) from brain metastases diagnosis was 11.3m(95% CI 7.2m – 15.3m). On univariate analysis, no prior WBRT(p = 0.038), higher KPS(p = 0.002) and systemic therapy after SRS(p &amp;lt; 0.001) predicted for improved OS. CONCLUSIONS We present here the largest study evaluating SRS for patients with ≥ 15 BMs. We found that SRS was safe, had favorable cognitive outcomes, and comparable survival outcomes to contemporary studies evaluating WBRT in this patient population. Our study supports further randomized studies comparing SRS and memory avoidance WBRT approaches for patients with ≥ 15 BMs.
PATH-25. EXPLORING THE PROGNOSTIC IMPLICATIONS OF MOLECULAR ALTERATIONS IN ASTROCYTOMAS USING COMPREHENSIVE GENOMIC PROFILING (CGP)
Authors: Nicholas McNamee, Frank Lin, Hao-Wen Sim, Chrstine Napier, David Thomas, John Simes, Subotheni Thavaneswaran
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Astrocytomas display molecular heterogeneity with prognostic implications for genomic alterations, including IDH, EGFR, TERT promoter and CDKN2A/B. Increasing access to comprehensive genomic profiling (CGP) provides an opportunity to characterize the genomic landscape of these tumors and their clinical implications. METHODS Patients with astrocytomas undergoing CGP through the Australian Molecular Screening and Therapeutics (MoST) precision oncology program between March 2017 and January 2022 were identified; the frequencies of genomic alterations were assessed. Associations between overall survival (OS) and alterations in EGFR, TERT promoter and/or CDKN2A/B were estimated using Kaplan-Meier methods. RESULTS 214 patients with astrocytomas were included. Median age was 49 years; majority were ECOG performance status 0-1 at screening (N=200/214, 93%) and histologically grade 4 (N=184/214, 86%). The median OS (mOS) for the cohort was 26.2mo (95%CI 24.0-31.5). For histologically grade 2/3 IDH-mutant tumors, mOS was 31.3mo (N=1) and 122.6mo (N=11, 95%CI 110-NA) for those with or without alterations in EGFR, TERT promoter and/or CDKN2A/B, respectively. For histologically grade 2/3 IDH-wildtype tumors, mOS was 19.9mo (N=7, 95%CI 15.8-NA) and 118.5mo (N=10, 95%CI 77.3-NA), respectively. For histologically grade 4 IDH-mutant tumors, mOS was 81.3mo (N=4, 95%CI 32.7-NA) and 82.8mo (N=15, 95%CI 71.0-NA), respectively. For histologically grade 4 IDH-wildtype tumors, mOS was 19.6mo (N=120 [56% TERT promoter, 42% EGFR, 14% CDKN2A/B], 95%CI 18.0-24.8) compared to 32.1mo (N=45, 95%CI 22.0-58.6; logrank P=0.0015), respectively. In grade 4 IDH-wildtype tumors additional co-occurring alterations involved PTEN (39%), TP53 (33%), NF1 (21%), RB1 (13%), CDK4 (13%) and PIK3CA (5%) genes. For the overall cohort, potentially actionable variants were seen in BRAF (5%), KIT (5%), MSH2 (2%), FGFR1 (1%) and FGFR3 (4%). Tumor mutational burden was ≥5 mutations/ megabase in 14%, without significant OS impact. CONCLUSION CGP provides additional prognostic information that complements histological grading. This demonstrates an emerging role in understanding the molecular heterogeneity of astrocytomas.
TMIC-70. A TRANSCRIPTIONALLY ACTIVE EPIGENETIC IMPRINTING OF THE JAK/STAT PATHWAY MEDIATED BY H3.3-G34 MUTATIONS IN PEDIATRIC HIGH-GRADE GLIOMA (PHGG) INDUCES AN IMMUNOREACTIVE TME
Authors: Santiago Haase, Maria Belen Garcia Fabiani, Kausjik Banerjee, Anzar Abdul Mujeeb, Yingxiang Li, Ziwen Zhu, Felipe Nunez, Jennifer Yu, Pedro Lowenstein, Maria Castro
Journal: Neuro-Oncology (2023)

Abstract Pediatric high-grade gliomas (pHGGs) stand as the primary cause of cancer-associated fatalities among children. Sixteen percent of pHGGs found in children and young adults present Gly34Arg/Val substitutions within the histone H3.3 (H3.3-G34R/V). Using a syngeneic, genetically engineered mouse model (GEMM) and human pHGG cells encoding H3.3-G34R, we showed that this mutation leads to downregulation of the DNA repair pathways and enhanced susceptibility to DNA damage. DNA damage response (DDR) inhibitors in vivo, further increased genetic instability, and activation of the cGAS-STING pathway, which induces the release of immune-stimulatory cytokines. We carried out an epigenetic analysis using ChIP-seq in our GEMM, and our findings indicate that this mutation triggers transcriptionally active chromatin states within genes linked to immune reactivity, particularly JAK-STAT signaling pathway genes. Correspondingly, G34-mutant pHGG cells release immune-activating cytokines that reprogram the immune cells within the tumor microenvironment (TME). Myeloid derived suppressor cells from G34-mutant pHGG are phenotypically less immunosuppressive than the MDCS form histone wild type pHGG. Moreover, G34-mutant pHGG TME exhibit higher frequency of CD8 T cells. Based on these findings, we assessed the efficacy of an adenoviral-mediated immunostimulatory gene therapy (GT). This therapy mediates expression of Flt3L within pHGG TME, which aids dendritic cell recruitment. Thymidine kinase (TK), converts ganciclovir (GSV) into a cytotoxic compound, leading to pHGG cells’ death. GT resulted in 60% of long-term survival in mice harboring G34R pHGG. The animals that survived due to the GT did not develop tumors after a rechallenge with G34R pHGG cells, demonstrating that the treatment induces antitumoral immunological memory. In conclusion, our findings suggest that G34-mutant pHGG patients could benefit from combined therapies that target genetic instability and stimulate the immune system. Funded by NIH/NINDS.
IMMU-12. TUMOR EXPRESSION OF CD83 PROMOTES IMMUNE CLEARANCE OF GLIOMA
Authors: Rachel Curry, Malcolm McDonald, Brittney Lozzi, Alexis Cervantes, Zhung-Fu Lee, Arif Harmanci, Anna Rosenbaum, Peihao He, Carrie Mohila, Benjamin Deneen, Akdes Serin-Harmanci, Ganesh Rao
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) remains deadly with minimal therapeutic improvement over the past decades. A hallmark of GBM is an immunosuppressive microenvironment, which includes anergic and suppressive T-cells. Antigen presentation is a critical component to successful activation of anti-tumor T cell responses and are dysregulated in GBM. To better understand how GBM cells modulate antigen presenting processes, we examined expression of antigen presentation genes in our single cell RNA-sequencing (scRNA-seq) cohort consisting of 18 GBM samples from 12 different human patients. Unexpectedly, we found a rare population of tumor cells with high expression of CD83, a marker of activated antigen presenting cells (APCs) that stabilizes MHC-II and CD86 expression. In an immunocompetent GFP-labeled piggyBac in utero electroporation (pB-IUE) model of GBM, we validated the existence of dually labeled CD83+GFP+ tumor cells using FACS image streaming. In vivo overexpression of CD83 (CD83OE) in tumor cells prolonged survival compared to control and CD83 knockout (CD83KO) tumors. In vitro, tumor cell lines derived from CD83OE tumors increased expansion and activation of co-cultured CD8+ T-cells whereas CD83KO tumors had a large population of immunosuppressive CD8+ T-cells. ELISAs of media from tumor cell lines revealed that CD83OE tumor cells secrete higher levels of the T cell activating cytokine, IL-2 than controls and CD83KO. scRNA-seq of pB-IUE tumors confirmed that CD83OE have increased activating cytokines compared to CD83KO and control tumors, and that CD83KO tumors had greater expression of immunosuppressive T-regulatory profiles. Intriguingly, we found that despite equal proliferative capacity of tumor cells both in vitro and in vivo conditions, CD83OE tumors were smaller, suggesting that CD83 expression by tumor cells stabilizes CD8+ T-cells to promote immune clearance of tumors. Collectively, our data suggests that enhancing tumor cell expression of antigen presenting markers such as CD83 may encourage immune-mediated clearance of GBM.
IMMU-24. SALVAGE IMMUNOTHERAPIES FOR REPLICATION REPAIR DEFICIENT (RRD) HIGH-GRADE GLIOMA FAILING ANTI-PD1 MONOTHERAPY: A REPORT FROM THE INTERNATIONAL RRD CONSORTIUM
Authors: Anirban Das, Nicholas Fernandez, Adrian Levine, Vanessa Bianchi, Lucie Stengs, Melissa Edwards, Liana Nobre, Derek Tsang, Birgit Ertl-Wagner, Daniel Morgenstern, Adam Shlien, Cynthia Hawkins, Eric Bouffet, Uri Tabori, Trevor Pugh
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Initial response to immune checkpoint inhibition (ICI) for DNA replication-repair deficient high-grade glioma (RRD-HGG) is encouraging. However, clinical/biologic implications of immune-directed approaches after failing ICI-monotherapy remain unknown. METHODS We performed an international study of patients managed using central review/treatment recommendations (2015-2021). Salvage after anti-PD1 failure included re-irradiation where feasible, and addition of anti-CTLA4 (ipilimumab), or a MEK-inhibitor (MEKi). Outcomes included radiological response (iRANO), toxicity, second progression-free (PFS2) and overall survival (OS2). Companion biomarkers were performed centrally. RESULTS Twenty among 75 patients treated on anti-PD1 monotherapy are progression-free at a median follow-up of 44.6-months. For 55 patients with relapsed/progressive tumors, continuation of ICI (n=38) resulted in median OS2 of 11.6-months (51% alive) versus 1.2-months when ICI was discontinued (n=17; no survivors, p&amp;lt; 0.001). Addition of ipilimumab (n=24) resulted in response/stable disease in 75% with median OS2 of 12.1-months. High autoimmune toxicities (54%) were observed, particularly in constitutional mismatch-repair deficiency patients. The addition of MEKi led to response in 3/5 patients with prolonged survival. The addition of re-irradiation improved median OS2, especially in tumors with lower mutation burden (p=0.002), and those who received ipilimumab (median OS2=33-months). Several biological insights were gained. Increased CTLA4 expression explained responses to ipilimumab. Re-irradiation responses were attributed to the absence of radio-resistant indel signature (ID8). Early radiological ‘flare’ was observed in 33% on combined immunotherapy and re-radiation. MEKi responses were associated with reinvigoration of peripheral immune response. Finally, delayed, sustained responses were observed in ultra-hypermutant RRD-HGG exhibiting changes in somatic mutational spectra. CONCLUSION These data suggest that the continuous mutagenesis renders hypermutant RRD-HGG susceptible to checkpoint inhibitors beyond initial progression. The combination with re-irradiation and additional immune/targeted agents can maximize survival in these children and young adults. Future research should focus on biology-driven rational immunotherapy combinations that also result in lower toxicity to maximize patient benefit.
STEM-22. SINGLE-CELL LINEAGE TRACING IN PRIMARY GLIOBLASTOMA REVEALS DISTINCT PROGENITOR SUBTYPES DRIVING INTRATUMORAL HETEROGENEITY
Authors: Elisa Fazzari, Daria Azizad, Weihong Ge, Matthew Li, Andrew Tum, Christopher Tse, Kunal Patel, Sree Deepthi Muthukrishnan, Harley Kornblum, David Nathanson, Aparna Bhaduri
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most common type of adult primary brain tumor with nearly a 100% rate of recurrence. One of the key clinical challenges is the vast degree of inter- and intra-tumoral variation in cell types and cell states, which change throughout the course of disease. Single-cell RNA-sequencing (scRNA-seq) studies in GBM samples have illuminated the complex landscape of cell type composition in primary and recurrent GBM, however these studies do not address how this diverse array of cell types developed or which cell populations are principally responsible for generating the heterogeneity and treatment resistance in the tumor. In this study, we implement a scRNA-seq compatible lineage tracing strategy, CellTagging, to track the behavior of individual tumor cells over time. Human GBM samples are dissociated immediately upon resection and infected with the CellTag DNA barcode library. The labeled cells are transplanted onto human cortical organoids, which facilitate the crucial normal-tumor cell interactions that enable GBM growth and invasion. After a period of proliferation, tumor cells are dissociated from the organoid and a fraction are harvested for scRNA-seq for transcriptomic and DNA barcode analysis. The remaining tumor cells are re-transplanted onto new organoids and harvested for scRNA-seq at later timepoints. Clonal relationships are determined by identifying cells with the same DNA barcode profile, and cell type characterizations are assigned via transcriptomic analysis. Transcriptomic profiling demonstrates the existence of multiple subtypes of tumor progenitors across timepoints. Strikingly, clonal analysis indicates that each progenitor subtype gives rise to numerous mature tumor cell types, suggesting multiple distinct lineages that contribute to tumor heterogeneity. Through differential expression analysis, we can predict which progenitors are most likely to drive which cell states. By introducing a treatment paradigm into our lineage tracing protocol, we identify tumor progenitor populations that contribute to treatment resistance.
DISP-17. BUILDING A MODEL PEDIATRIC NEURO-ONCOLOGY PROGRAM IN SUB-SAHARAN AFRICA AND ITS IMPACT
Authors: Victoria Mwebe Katasi, Deo Munube, Ruth Namazzi, Cathy Nabaggala, Luutu Israel, Julie Ssekabunga, Peter Ssenyonga, Angelina Kakooza Mwesigye, Murali Chintagumpala, Peter Wasswa Muwonge, Ann Akullo, Annet Nakirulu, Phillip Kasirye, Ronald Naitala, Theresa Piloya
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Central nervous system tumors are the most common solid tumors in children and the second commonest childhood cancer globally. We describe the establishment of the first dedicated comprehensive pediatric neuro-oncology treatment center that may serve as a model for others in low-resource settings and the impact of this initiative. METHODS This is a descriptive interim report of a pediatric neuro-oncology capacity building program in the SSA setting established in March 2019 at Mulago National Referral Hospital in Uganda, including a retrospective study conducted at Mulago National referral Hospital, in patients below 18 years of age admitted with a radiological diagnosis of a brain tumor from March 2019 to March 2023, to demonstrate the impact of this program. The program is a collaboration between Makerere University, Mulago National Referral Hospital, Texas children's Hospital/Baylor College of Medicine, and other academic and philanthropy partners in North America and Europe. RESULTS A total of 14 pediatric oncologists have been trained over 6 years, with one further training in neuro-oncology. Multidisciplinary management involving local experts from Uganda and experts from Texas Children's Hospital has been strengthened. Between March 2019 and March 2023, 121 children were diagnosed radiologically with brain tumors. Majority (57%) of these patients were males. The commonest symptom at presentation was headache (42%). Most of the patients (52%) had infratentorial tumors. The commonest diagnosis was glioma (38%), craniopharyngioma (26%), medulloblastoma (11%). Fifty-two patients had surgical resection and a histological diagnosis. Ten percent of patients had no diagnosis. Radiotherapy was received by 24(20%) patients. Twenty patients received chemotherapy. Sixty-six are alive and attending clinic. The overall one-year survival was 63%(95%CI(50.3-73.4). CONCLUSION Capacity to improve the suspicion, referral, diagnosis and comprehensive care for children with central nervous system tumors in low-resource settings can be improved through innovative collaborations.
RBIO-05. MITOTIC ENRICHMENT AS AN EFFICIENT RADIOSENSITIZATION STRATEGY FOR INTRACRANIAL TUMORS
Authors: Mark de Gooijer, Hilal Colakoglu, Ceren Citirikkaya, Daria Fedorushkova, Amal El Ouazani, Ronak Shah, Michael Meel, Esther Hulleman, Gerben Borst, Olaf van Tellingen
Journal: Neuro-Oncology (2023)

Abstract Radiotherapy remains one of the most effective modalities for anticancer treatment and part of standard of care for many primary and metastatic brain tumors. Boosting the efficacy of radiotherapy is therefore a logical avenue to improve patient survival. We have developed a radiosensitization strategy called ‘induction of mitotic enrichment’. It has long been known that the radiosensitivity of a cell depends on the phase of the cell cycle and that mitotic cells are especially vulnerable. Enriching the tumor for mitotic cells by arresting them during division prior to each radiotherapy fraction should therefore render the tumor population more sensitive to irradiation. Ideally, induction of mitotic enrichment should be reversible and non-cytotoxic to prevent healthy tissue toxicity and be compatible with clinically applied fractionated radiotherapy regimens. We have now identified an orally available targeted tubulin polymerization inhibitor that can achieve repeated and reversible mitotic enrichment for up to 10 hours prior to radiotherapy, without causing cytotoxicity in vitro or healthy tissue toxicity in vivo. This tubulin inhibitor (ABT-751) efficiently radiosensitizes a range of preclinical tumor models representing adult and pediatric, primary and metastatic brain tumors. Importantly, ABT-751 also improves survival in mouse models of adult glioblastoma (GBM), but only in a mitotic enrichment setup when given several hours prior to radiotherapy to allow accumulation in mitosis. Of note, induction of mitotic enrichment does not exacerbate healthy tissue toxicity. To conclude, induction of mitotic enrichment by ABT-751 radiosensitizes adult GBM to fractionated radiotherapy. We are currently expanding our preclinical development of mitotic enrichment as a radiosensitization strategy to other targets and cancers and have designed a phase 0/I trial for adult GBM to demonstrate induction of mitotic enrichment and tolerability when combined with radiotherapy. We expect to start enrollment in this trial soon.